Mutations in Ras proteins are found in more than 30% of all human cancers, including greater than 90% of pancreatic cancers, 50% of colon cancers and 30% of lung adenocarcinoma. Ras genes encode a family of guanine nucleotide-binding proteins that, to be functional, must be associated with the inner surface of the plasma membrane. Ras proteins lack the conventional transmembrane or hydrophobic sequences associated with other membrane-associated proteins and are initially synthesized as soluble, cytoplasmic proteins. Their membrane association is triggered by a series of post-translational processing steps involving a carboxy terminal motif referred to as the CaaX box. The CaaX box consists of a conserved cysteine residue, two aliphatic amino acids, and a carboxy-terminal amino acid residue. The post-translational steps required for the attachment of Ras proteins to the inner plasma membrane are: (i) the transfer of farnesyl pyrophosphate (a 15-carbon isoprene lipid) or geranylgeranyl moiety (a four-isoprene unit molecule) onto the cysteine in the carboxy terminal "CaaX" motif by a prenyl transferase i.e., farnesyl protein transferase (FPT) or geranylgeranyl protein transferase (GGPT); (ii) proteolytic cleavage of the three carboxy terminal amino acid residues by Ras Converting Endoprotease (RCE); and(iii) methylation of the resulting carboxy terminal prenyl cysteine residue by prenyl cysteine specific Carboxymethyltransferase (PC-CMT).
Cleavage by RCE modulates Ras function in yeast, therefore it may be a novel target to modulate oncogenic Ras in human tumors. Null mutations in RCE cause no obvious growth or viable defects, whereas mutations in FPT cause cells to be either growth defective or dead. If these results in yeast translate to human cells, inhibitors of RCE may be safer therapeutic agents than inhibitors of FPT.
Accordingly, the identification of human RCE will provide a critical tool necessary for the development of inhibitors of RCE which represent novel therapeutic agents for the treatment of human cancers.